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Science 303 (5657): 523-527

Copyright © 2004 by the American Association for the Advancement of Science

Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins

Dapeng Zhou,1* Carlos Cantu, III,2* Yuval Sagiv,1 Nicolas Schrantz,2 Ashok B. Kulkarni,3 Xiaoyang Qi,4 Don J. Mahuran,5 Carlos R. Morales,6 Gregory A. Grabowski,4 Kamel Benlagha,1 Paul Savage,7 Albert Bendelac,1{dagger} Luc Teyton2{dagger}

Abstract: It is now established that CD1 molecules present lipid antigens to T cells, although it is not clear how the exchange of lipids between membrane compartments and the CD1 binding groove is assisted. We report that mice deficient in prosaposin, the precursor to a family of endosomal lipid transfer proteins (LTP), exhibit specific defects in CD1d-mediated antigen presentation and lack V{alpha}14 NKT cells. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1. Transient complexes between CD1, lipid, and LTP suggested a "tug-of-war" model in which lipid exchange between CD1 and LTP is on the basis of their respective affinities for lipids. LTPs constitute a previously unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens.

1 Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
2 Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
3 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
4 Children Hospital Medical Center, Cincinnati, OH 45229–3039, USA.
5 Department of Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
6 Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 2B2, Canada.
7 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602–5700, USA.

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* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: abendela{at}bsd.uchicago.edu (A.B.); lteyton{at}scripps.edu (L.T.)


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